The central event after traumatic brain injury (TI) is the transient, or ongoing impairment of electrophysiological function, manifest as coma, "concussion" or neurological deficit. Persistent reduction in the Resting Membrane Potential, and consequent failure to adequately re-polarize neuronal and axonal membranes, are the most likely mechanisms for eliciting these effects. This application revolves around the central hypothesis that mitochondrial dysfunction and reduced ionic pumping, leading bioenergetic failure, is the major limiting factor, determining neuronal and axonal recovery after TBI. In this application, we build upon our previous studies, demonstrating massive excitatory neurotransmitter release after TBI, leading to calcium influx. This in turn damages mitochondria, neurofilaments, and second-messenger mediated ion channels, among many other events. These issues will be explored in the clinic and laboratory settings. Specifically, in rat TBI models, we will use immunohistochemistry, molecular biology, electrophysiology, and behavioral testing to validate the hypothesis that calcium-mediated damage to inhibitory GABA Cl channels exacerbates neuronal damage, and thus worsens outcomes, and that GABA agonists improve outcome. We will directly measure cytochrome oxidase activity, to show that mitochondria are functionally impaired after TBI, and we will posit that specific blockade of the Mitochondria Transition Pore (MPT) with Cyclosporin A, will prevent these changes, and improve outcome. In severely head injured patients, simultaneous microdialysis, and a new coaxial depth electrode, together with a tissue oxygen/CO2/pH sensor system, will be placed in the same brain region to test the effect of increased oxygen tension, and Cyclosporin A under the interplay of neurochemical and neurophysiological events. We will use AVDO2, AVD lactate, and AVD glucose to assess global therapy effects, and relate them to CBF and MRI parameters. Finally, we will use MRI water mapping, Diffusion Weighted Imaging, and CBF mapping, to show that the brain swelling, which almost always follows TBI is due to cytotoxic edema. These methods will also test the hypothesis that Cyclosporin A will ameliorate cytotoxic edema, and that N Acetyl Aspartate spectroscopy will constitute a "surrogate marker" for mitochondrialy, and neuronal damage in human TBI. Thus, these novel techniques, through a tightly integrated set of laboratory and clinical studies, will yield new mechanistic insights, and specifically evaluate Cyclosporin A and several other putative new therapies in TBI.